Metformin Corrects Glucose Metabolism Reprogramming and NLRP3 Inflammasome-Induced Pyroptosis via Inhibiting the TLR4/NF-κB/PFKFB3 Signaling in Trophoblasts: Implication for a Potential Therapy of Preeclampsia

NOD-like receptor family, pyrin domain-containing protein 3 (NLRP3) inflammasome-mediated pyroptosis is a crucial event in the preeclamptic pathogenesis, tightly linked with the uteroplacental TLR4/NF-κB signaling. Trophoblastic glycometabolism reprogramming has now been noticed in the preeclampsia...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Yang Zhang, Weifang Liu, Yanqi Zhong, Qi Li, Mengying Wu, Liu Yang, Xiaoxia Liu, Li Zou
Formato:	article
Lenguaje:	EN
Publicado:	Hindawi Limited 2021
Materias:	Cytology QH573-671
Acceso en línea:	https://doaj.org/article/a51762de135b4a77a6799778eb7af2d6
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:a51762de135b4a77a6799778eb7af2d6
record_format	dspace
spelling	oai:doaj.org-article:a51762de135b4a77a6799778eb7af2d62021-11-22T01:10:13ZMetformin Corrects Glucose Metabolism Reprogramming and NLRP3 Inflammasome-Induced Pyroptosis via Inhibiting the TLR4/NF-κB/PFKFB3 Signaling in Trophoblasts: Implication for a Potential Therapy of Preeclampsia1942-099410.1155/2021/1806344https://doaj.org/article/a51762de135b4a77a6799778eb7af2d62021-01-01T00:00:00Zhttp://dx.doi.org/10.1155/2021/1806344https://doaj.org/toc/1942-0994NOD-like receptor family, pyrin domain-containing protein 3 (NLRP3) inflammasome-mediated pyroptosis is a crucial event in the preeclamptic pathogenesis, tightly linked with the uteroplacental TLR4/NF-κB signaling. Trophoblastic glycometabolism reprogramming has now been noticed in the preeclampsia pathogenesis, plausibly modulated by the TLR4/NF-κB signaling as well. Intriguingly, cellular pyroptosis and metabolic phenotypes may be inextricably linked and interacted. Metformin (MET), a widely accepted NF-κB signaling inhibitor, may have therapeutic potential in preeclampsia while the underlying mechanisms remain unclear. Herein, we investigated the role of MET on trophoblastic pyroptosis and its relevant metabolism reprogramming. The safety of pharmacologic MET concentration to trophoblasts was verified at first, which had no adverse effects on trophoblastic viability. Pharmacological MET concentration suppressed NLRP3 inflammasome-induced pyroptosis partly through inhibiting the TLR4/NF-κB signaling in preeclamptic trophoblast models induced via low-dose lipopolysaccharide. Besides, MET corrected the glycometabolic reprogramming and oxidative stress partly via suppressing the TLR4/NF-κB signaling and blocking transcription factor NF-κB1 binding on the promoter PFKFB3, a potent glycolytic accelerator. Furthermore, PFKFB3 can also enhance the NF-κB signaling, reduce NLRP3 ubiquitination, and aggravate pyroptosis. However, MET suppressed pyroptosis partly via inhibiting PFKFB3 as well. These results provided that the TLR4/NF-κB/PFKFB3 pathway may be a novel link between metabolism reprogramming and NLRP3 inflammasome-induced pyroptosis in trophoblasts. Further, MET alleviates the NLRP3 inflammasome-induced pyroptosis, which partly relies on the regulation of TLR4/NF-κB/PFKFB3-dependent glycometabolism reprogramming and redox disorders. Hence, our results provide novel insights into the pathogenesis of preeclampsia and propose MET as a potential therapy.Yang ZhangWeifang LiuYanqi ZhongQi LiMengying WuLiu YangXiaoxia LiuLi ZouHindawi LimitedarticleCytologyQH573-671ENOxidative Medicine and Cellular Longevity, Vol 2021 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Cytology QH573-671
spellingShingle	Cytology QH573-671 Yang Zhang Weifang Liu Yanqi Zhong Qi Li Mengying Wu Liu Yang Xiaoxia Liu Li Zou Metformin Corrects Glucose Metabolism Reprogramming and NLRP3 Inflammasome-Induced Pyroptosis via Inhibiting the TLR4/NF-κB/PFKFB3 Signaling in Trophoblasts: Implication for a Potential Therapy of Preeclampsia
description	NOD-like receptor family, pyrin domain-containing protein 3 (NLRP3) inflammasome-mediated pyroptosis is a crucial event in the preeclamptic pathogenesis, tightly linked with the uteroplacental TLR4/NF-κB signaling. Trophoblastic glycometabolism reprogramming has now been noticed in the preeclampsia pathogenesis, plausibly modulated by the TLR4/NF-κB signaling as well. Intriguingly, cellular pyroptosis and metabolic phenotypes may be inextricably linked and interacted. Metformin (MET), a widely accepted NF-κB signaling inhibitor, may have therapeutic potential in preeclampsia while the underlying mechanisms remain unclear. Herein, we investigated the role of MET on trophoblastic pyroptosis and its relevant metabolism reprogramming. The safety of pharmacologic MET concentration to trophoblasts was verified at first, which had no adverse effects on trophoblastic viability. Pharmacological MET concentration suppressed NLRP3 inflammasome-induced pyroptosis partly through inhibiting the TLR4/NF-κB signaling in preeclamptic trophoblast models induced via low-dose lipopolysaccharide. Besides, MET corrected the glycometabolic reprogramming and oxidative stress partly via suppressing the TLR4/NF-κB signaling and blocking transcription factor NF-κB1 binding on the promoter PFKFB3, a potent glycolytic accelerator. Furthermore, PFKFB3 can also enhance the NF-κB signaling, reduce NLRP3 ubiquitination, and aggravate pyroptosis. However, MET suppressed pyroptosis partly via inhibiting PFKFB3 as well. These results provided that the TLR4/NF-κB/PFKFB3 pathway may be a novel link between metabolism reprogramming and NLRP3 inflammasome-induced pyroptosis in trophoblasts. Further, MET alleviates the NLRP3 inflammasome-induced pyroptosis, which partly relies on the regulation of TLR4/NF-κB/PFKFB3-dependent glycometabolism reprogramming and redox disorders. Hence, our results provide novel insights into the pathogenesis of preeclampsia and propose MET as a potential therapy.
format	article
author	Yang Zhang Weifang Liu Yanqi Zhong Qi Li Mengying Wu Liu Yang Xiaoxia Liu Li Zou
author_facet	Yang Zhang Weifang Liu Yanqi Zhong Qi Li Mengying Wu Liu Yang Xiaoxia Liu Li Zou
author_sort	Yang Zhang
title	Metformin Corrects Glucose Metabolism Reprogramming and NLRP3 Inflammasome-Induced Pyroptosis via Inhibiting the TLR4/NF-κB/PFKFB3 Signaling in Trophoblasts: Implication for a Potential Therapy of Preeclampsia
title_short	Metformin Corrects Glucose Metabolism Reprogramming and NLRP3 Inflammasome-Induced Pyroptosis via Inhibiting the TLR4/NF-κB/PFKFB3 Signaling in Trophoblasts: Implication for a Potential Therapy of Preeclampsia
title_full	Metformin Corrects Glucose Metabolism Reprogramming and NLRP3 Inflammasome-Induced Pyroptosis via Inhibiting the TLR4/NF-κB/PFKFB3 Signaling in Trophoblasts: Implication for a Potential Therapy of Preeclampsia
title_fullStr	Metformin Corrects Glucose Metabolism Reprogramming and NLRP3 Inflammasome-Induced Pyroptosis via Inhibiting the TLR4/NF-κB/PFKFB3 Signaling in Trophoblasts: Implication for a Potential Therapy of Preeclampsia
title_full_unstemmed	Metformin Corrects Glucose Metabolism Reprogramming and NLRP3 Inflammasome-Induced Pyroptosis via Inhibiting the TLR4/NF-κB/PFKFB3 Signaling in Trophoblasts: Implication for a Potential Therapy of Preeclampsia
title_sort	metformin corrects glucose metabolism reprogramming and nlrp3 inflammasome-induced pyroptosis via inhibiting the tlr4/nf-κb/pfkfb3 signaling in trophoblasts: implication for a potential therapy of preeclampsia
publisher	Hindawi Limited
publishDate	2021
url	https://doaj.org/article/a51762de135b4a77a6799778eb7af2d6
work_keys_str_mv	AT yangzhang metformincorrectsglucosemetabolismreprogrammingandnlrp3inflammasomeinducedpyroptosisviainhibitingthetlr4nfkbpfkfb3signalingintrophoblastsimplicationforapotentialtherapyofpreeclampsia AT weifangliu metformincorrectsglucosemetabolismreprogrammingandnlrp3inflammasomeinducedpyroptosisviainhibitingthetlr4nfkbpfkfb3signalingintrophoblastsimplicationforapotentialtherapyofpreeclampsia AT yanqizhong metformincorrectsglucosemetabolismreprogrammingandnlrp3inflammasomeinducedpyroptosisviainhibitingthetlr4nfkbpfkfb3signalingintrophoblastsimplicationforapotentialtherapyofpreeclampsia AT qili metformincorrectsglucosemetabolismreprogrammingandnlrp3inflammasomeinducedpyroptosisviainhibitingthetlr4nfkbpfkfb3signalingintrophoblastsimplicationforapotentialtherapyofpreeclampsia AT mengyingwu metformincorrectsglucosemetabolismreprogrammingandnlrp3inflammasomeinducedpyroptosisviainhibitingthetlr4nfkbpfkfb3signalingintrophoblastsimplicationforapotentialtherapyofpreeclampsia AT liuyang metformincorrectsglucosemetabolismreprogrammingandnlrp3inflammasomeinducedpyroptosisviainhibitingthetlr4nfkbpfkfb3signalingintrophoblastsimplicationforapotentialtherapyofpreeclampsia AT xiaoxialiu metformincorrectsglucosemetabolismreprogrammingandnlrp3inflammasomeinducedpyroptosisviainhibitingthetlr4nfkbpfkfb3signalingintrophoblastsimplicationforapotentialtherapyofpreeclampsia AT lizou metformincorrectsglucosemetabolismreprogrammingandnlrp3inflammasomeinducedpyroptosisviainhibitingthetlr4nfkbpfkfb3signalingintrophoblastsimplicationforapotentialtherapyofpreeclampsia
_version_	1718418360357617664

Metformin Corrects Glucose Metabolism Reprogramming and NLRP3 Inflammasome-Induced Pyroptosis via Inhibiting the TLR4/NF-κB/PFKFB3 Signaling in Trophoblasts: Implication for a Potential Therapy of Preeclampsia

Ejemplares similares